Non Insulin Dependent Diabetes, Pregnancy
Conditions
Keywords
Non Insulin Dependent Diabetes, Pregnancy
Brief summary
Many women come into pregnancy with diabetes that is controlled with either Metformin or diet control; however, the current standard of care for the treatment of preexisting diabetes in pregnancy is insulin. Metformin is widely used in the non-pregnant population for glycemic control, and has been used in pregnancy for other indications without adverse maternal or fetal outcomes. What remains unproven is the ability of Metformin to adequately control glucose in women during pregnancy. Our goal is to randomize 100 women who enter pregnancy with diabetes that is controlled by either diet or an oral agent and women who are found to have an abnormal glucose challenge test at less than 20 weeks to either standard treatment with weight based Regular and neutral protamine Hagedorn (NPH) insulin or Metformin. Our hypothesis is that Metformin will provide glycemic control that is equivalent to insulin in these women.
Interventions
DRUGMetformin
Women randomized to the Experimental arm will receive standard diet and glucose self-monitoring education. They will be initiated on Metformin 500 BID if they were medication naïve, or will be continued on their current dosage of Metformin if they were taking it prior to pregnancy. At each clinic visit fasting and one hour post prandial glucose values will be reviewed, and dosage will be titrated to a maximum of 2250mg/day to achieve target glycemic control. If glycemic control can not be achieved with Metformin as a single agent insulin will be added.
DRUGInsulin
Women randomized to the Insulin group will receive standard diet and glycemic monitoring education. They will be initiated on weight based Regular and NPH insulin at a total dosage of 0.7units/kg in the first trimester or 0.8units/kg in the second trimester divided as 2/3 of the total dosage (with 2/3 given as NPH and 1/3 given as Regular) administered before breakfast and 1/3 of the total dosage (with 1/2 given as NPH and 1/2 given as Regular)administered with dinner. At each clinic visit fasting and one hour post prandial glucose values will be reviewed, and dosage will be titrated to achieve optimal glycemic control with fasting values \<90 and one hour post prandial values \<130.
Sponsors
WakeMed Health and Hospitals
University of North Carolina, Chapel Hill
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
FEMALE
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Receiving prenatal care at University of North Carolina (UNC), Chapel Hill Obstetric clinics and planning delivery at UNC Women's Hospital * Diagnosis of Diabetes prior to pregnancy with use of an oral hypoglycemic agent or dietary control * Diagnosis of early gestational diabetes prior to 20 weeks gestation via abnormal 3 hour glucose challenge testing using the national diabetes data group (NDDG)criteria * Less than 24 weeks at study enrollment * Singleton or twin pregnancy * English or Spanish speaking * Able to give informed consent
Exclusion criteria
* End organ complications of diabetes (retinopathy, renal insufficiency, etc.) * Prior need for insulin for glycemic control * History of diabetic ketoacidosis (DKA) or hyperosmolar state * Prior adverse reaction (ie. lactic acidosis) or allergy to Metformin * Kidney or liver disease * Significant medical co-morbidities (lupus, cystic fibrosis, etc.) Hypertension controlled on one medication, well controlled asthma, and well controlled thyroid disease are not excluded.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Blood Glucose Measurements | Daily fasting and 1-hr post prandial measures were taken from time of enrollment until delivery | Patients self monitored glucose measures throughout pregnancy to aid glycemic control. Fasting morning measures and postprandial measures were taken at 1 hour after breakfast, lunch, and dinner. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Maternal Weight Gain | Baseline throughout pregnancy until last prenatal visit. | — |
| Number of Babies With Neonatal Hypoglycemia | Time of delivery through hospital discharge | Initial neonatal glucose \< 40 mg/dL |
| Glycosylated Hemoglobin (HbA1c) by Pregnancy Trimester | 1st, 2nd, and 3rd trimester | — |
| Number of Patients With Obstetric Complications | Throughout pregnancy until hospital discharge following delivery. | Maternal complications were stillbirths, major malformations, shoulder dystocia, or postpartum hemorrhage requiring transfusion. |
| Percent of Glucose Values at or Below Postprandial Goal (<130 mg/dL) | Baseline throughout pregnancy until time of delivery | NUMBER OF ASSESSMENTS OF POSTPRANDIAL GLUCOSE VALUES \<130 |
| Number of Episodes Maternal Hypoglycemia | Baseline throughout pregnancy until time of delivery | Maternal glucose \< 60 mg/dL |
| Number of Babies With Adverse Neonatal Outcomes | Delivery until hospital discharge | Resuscitation in the delivery room, preterm birth \< 37 weeks, neonatal intensive care unit care, birth injury or diagnosis of neonatal complication, glucose infusion, antibiotics, or phototherapy. |
| Percent of Glucose Values at or Below Fasting Goal (<95 mg/dL) | Baseline throughout pregnancy until time of delivery | NUMBER OF ASSESSMENTS OF FASTING GLUCOSE VALUES \<95 |
Countries
United States
Participant flow
Recruitment details
Recruitment occurred at two hospitals from July 2008 through March 2010 at one and from January 2009 through December 2009 at the other.
Participants by arm
| Arm | Count |
|---|---|
| Metformin Patients received standard diet and glucose self-monitoring education. Medication naive patients were initiated on Metformin 500 BID or were continued on their current dosage of Metformin if taking prior to pregnancy. Self-reported glucose values were reviewed during each clinic visit and Metformin dosage was titrated up to a maximum of 2250 mg/day as needed for glycemic control. Insulin was added to those not achieving glycemic control with Metformin alone. | 14 |
| Insulin Patients received standard diet and glycemic monitoring education. They were started on weight-based Regular and NPH insulin at a total dosage of 0.7units/kg in the first trimester or 0.8units/kg in the second trimester divided as 2/3 of the total dosage (with 2/3 given as NPH and 1/3 given as Regular) administered before breakfast and 1/3 of the total dosage (with 1/2 given as NPH and 1/2 given as Regular) administered with dinner. Self-reported glucose values were reviewed during each clinic visit and insulin dosage was titrated to achieve optimal glycemic control with fasting values \<90 and one hour post prandial values \<130. | 14 |
| Total | 28 |
Baseline characteristics
| Characteristic | Insulin | Metformin | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 14 Participants | 14 Participants | 28 Participants |
| Age, Continuous | 29.7 years STANDARD_DEVIATION 4.1 | 35.7 years STANDARD_DEVIATION 2.6 | 32.7 years STANDARD_DEVIATION 4.6 |
| Region of Enrollment United States | 14 participants | 14 participants | 28 participants |
| Sex: Female, Male Female | 14 Participants | 14 Participants | 28 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 0 / 14 | 0 / 14 |
| serious Total, serious adverse events | 1 / 14 | 0 / 14 |
Outcome results
Primary
Blood Glucose Measurements
Patients self monitored glucose measures throughout pregnancy to aid glycemic control. Fasting morning measures and postprandial measures were taken at 1 hour after breakfast, lunch, and dinner.
Time frame: Daily fasting and 1-hr post prandial measures were taken from time of enrollment until delivery
Population: For 1 infant in each group, the initial neonatal glucose value was missing.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Metformin | Blood Glucose Measurements | Fasting throughout enrollment | 97.38 mg/dL |
| Metformin | Blood Glucose Measurements | Fasting 18-20 weeks | 97.00 mg/dL |
| Metformin | Blood Glucose Measurements | Fasting 28-30 weeks | 92.43 mg/dL |
| Metformin | Blood Glucose Measurements | Fasting 36-38 weeks | 89.49 mg/dL |
| Metformin | Blood Glucose Measurements | Postprandial throughout enrollment | 120.40 mg/dL |
| Metformin | Blood Glucose Measurements | Postprandial 18-20 weeks | 118.40 mg/dL |
| Metformin | Blood Glucose Measurements | Postprandial 28-30 weeks | 119.00 mg/dL |
| Metformin | Blood Glucose Measurements | Postprandial 36-38 weeks | 122.59 mg/dL |
| Insulin | Blood Glucose Measurements | Postprandial 36-38 weeks | 125.25 mg/dL |
| Insulin | Blood Glucose Measurements | Fasting throughout enrollment | 95.04 mg/dL |
| Insulin | Blood Glucose Measurements | Postprandial throughout enrollment | 128.62 mg/dL |
| Insulin | Blood Glucose Measurements | Fasting 18-20 weeks | 92.38 mg/dL |
| Insulin | Blood Glucose Measurements | Postprandial 28-30 weeks | 126.45 mg/dL |
| Insulin | Blood Glucose Measurements | Fasting 28-30 weeks | 90.64 mg/dL |
| Insulin | Blood Glucose Measurements | Postprandial 18-20 weeks | 120.46 mg/dL |
| Insulin | Blood Glucose Measurements | Fasting 36-38 weeks | 85.18 mg/dL |
Secondary
Glycosylated Hemoglobin (HbA1c) by Pregnancy Trimester
Time frame: 1st, 2nd, and 3rd trimester
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Metformin | Glycosylated Hemoglobin (HbA1c) by Pregnancy Trimester | 1st trimester | 5.8 percentage of glycosolated hemoglobin |
| Metformin | Glycosylated Hemoglobin (HbA1c) by Pregnancy Trimester | 2nd trimester | 5.6 percentage of glycosolated hemoglobin |
| Metformin | Glycosylated Hemoglobin (HbA1c) by Pregnancy Trimester | 3rd trimester | 5.9 percentage of glycosolated hemoglobin |
| Insulin | Glycosylated Hemoglobin (HbA1c) by Pregnancy Trimester | 1st trimester | 6.2 percentage of glycosolated hemoglobin |
| Insulin | Glycosylated Hemoglobin (HbA1c) by Pregnancy Trimester | 2nd trimester | 5.5 percentage of glycosolated hemoglobin |
| Insulin | Glycosylated Hemoglobin (HbA1c) by Pregnancy Trimester | 3rd trimester | 5.6 percentage of glycosolated hemoglobin |
Secondary
Maternal Weight Gain
Time frame: Baseline throughout pregnancy until last prenatal visit.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Metformin | Maternal Weight Gain | 0.28 kg/week |
| Insulin | Maternal Weight Gain | 0.30 kg/week |
Secondary
Number of Babies With Adverse Neonatal Outcomes
Resuscitation in the delivery room, preterm birth \< 37 weeks, neonatal intensive care unit care, birth injury or diagnosis of neonatal complication, glucose infusion, antibiotics, or phototherapy.
Time frame: Delivery until hospital discharge
Population: For 1 infant in the metformin group, the adverse neonatal outcome data was missing.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Metformin | Number of Babies With Adverse Neonatal Outcomes | 4 number of babies |
| Insulin | Number of Babies With Adverse Neonatal Outcomes | 7 number of babies |
Secondary
Number of Babies With Neonatal Hypoglycemia
Initial neonatal glucose \< 40 mg/dL
Time frame: Time of delivery through hospital discharge
Population: For 1 infant in each group, the initial neonatal glucose value was missing.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Metformin | Number of Babies With Neonatal Hypoglycemia | 2 Number of babies |
| Insulin | Number of Babies With Neonatal Hypoglycemia | 0 Number of babies |
Secondary
Number of Episodes Maternal Hypoglycemia
Maternal glucose \< 60 mg/dL
Time frame: Baseline throughout pregnancy until time of delivery
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Metformin | Number of Episodes Maternal Hypoglycemia | 1 Number of episodes |
| Insulin | Number of Episodes Maternal Hypoglycemia | 7 Number of episodes |
Secondary
Number of Patients With Obstetric Complications
Maternal complications were stillbirths, major malformations, shoulder dystocia, or postpartum hemorrhage requiring transfusion.
Time frame: Throughout pregnancy until hospital discharge following delivery.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Metformin | Number of Patients With Obstetric Complications | 0 participants |
| Insulin | Number of Patients With Obstetric Complications | 0 participants |
Secondary
Percent of Glucose Values at or Below Fasting Goal (<95 mg/dL)
NUMBER OF ASSESSMENTS OF FASTING GLUCOSE VALUES \<95
Time frame: Baseline throughout pregnancy until time of delivery
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Metformin | Percent of Glucose Values at or Below Fasting Goal (<95 mg/dL) | Throughout enrollment; n=1634, 1432 | 48 percent of glucose values |
| Metformin | Percent of Glucose Values at or Below Fasting Goal (<95 mg/dL) | 18-20 weeks; n=148, 259 | 42 percent of glucose values |
| Metformin | Percent of Glucose Values at or Below Fasting Goal (<95 mg/dL) | 28-30 weeks; n=253, 201 | 64 percent of glucose values |
| Metformin | Percent of Glucose Values at or Below Fasting Goal (<95 mg/dL) | 36-38 weeks; n=115, 83 | 76 percent of glucose values |
| Insulin | Percent of Glucose Values at or Below Fasting Goal (<95 mg/dL) | 36-38 weeks; n=115, 83 | 96 percent of glucose values |
| Insulin | Percent of Glucose Values at or Below Fasting Goal (<95 mg/dL) | Throughout enrollment; n=1634, 1432 | 58 percent of glucose values |
| Insulin | Percent of Glucose Values at or Below Fasting Goal (<95 mg/dL) | 28-30 weeks; n=253, 201 | 62 percent of glucose values |
| Insulin | Percent of Glucose Values at or Below Fasting Goal (<95 mg/dL) | 18-20 weeks; n=148, 259 | 64 percent of glucose values |
Secondary
Percent of Glucose Values at or Below Postprandial Goal (<130 mg/dL)
NUMBER OF ASSESSMENTS OF POSTPRANDIAL GLUCOSE VALUES \<130
Time frame: Baseline throughout pregnancy until time of delivery
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Metformin | Percent of Glucose Values at or Below Postprandial Goal (<130 mg/dL) | Throughout enrollment; n=4195, 3796 | 69 percent of glucose values |
| Metformin | Percent of Glucose Values at or Below Postprandial Goal (<130 mg/dL) | 18-20 weeks; n=368, 428 | 72 percent of glucose values |
| Metformin | Percent of Glucose Values at or Below Postprandial Goal (<130 mg/dL) | 28-30 weeks; n=652, 559 | 71 percent of glucose values |
| Metformin | Percent of Glucose Values at or Below Postprandial Goal (<130 mg/dL) | 36-38 weeks; n=272,228 | 66 percent of glucose values |
| Insulin | Percent of Glucose Values at or Below Postprandial Goal (<130 mg/dL) | 36-38 weeks; n=272,228 | 65 percent of glucose values |
| Insulin | Percent of Glucose Values at or Below Postprandial Goal (<130 mg/dL) | Throughout enrollment; n=4195, 3796 | 61 percent of glucose values |
| Insulin | Percent of Glucose Values at or Below Postprandial Goal (<130 mg/dL) | 28-30 weeks; n=652, 559 | 58 percent of glucose values |
| Insulin | Percent of Glucose Values at or Below Postprandial Goal (<130 mg/dL) | 18-20 weeks; n=368, 428 | 67 percent of glucose values |